On April 3, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery (Press release, Daiichi Sankyo, APR 3, 2019, View Source [SID1234535008]). TGCT is also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS).

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Validation confirms that the application is complete and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The EU MAA is based on results of the pivotal phase 3 ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT, which met its primary endpoint of overall response rate. Results of the phase 3 ENLIVEN study were presented during an oral presentation at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

"We are pleased that review of our submission for pexidartinib in Europe is now underway, and we look forward to working with the EMA to potentially offer the first approved systemic therapy to carefully-selected patients with TGCT," said Dale Shuster, Ph.D., Executive Director, Global Oncology R&D, Daiichi Sankyo.

"We are excited about the first-in-class potential of pexidartinib, another targeted therapy discovered by Plexxikon," said Gideon Bollag, Ph.D., Chief Executive Officer of Plexxikon Inc., Daiichi Sankyo’s small molecule structure-guided R&D center in Berkeley, CA and a member of the Daiichi Sankyo Group. "Our drug discovery process uses structural data and a specialized scaffold-like screening library to identify and optimize novel drug candidates."

The New Drug Application (NDA) for pexidartinib is currently under Priority Review in the U.S., and the FDA is expected to make a decision on approval by August 3, 2019.

ENLIVEN is a pivotal, double-blind, randomized, global multi-center phase 3 study that evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/day for 2 weeks followed by 800 mg/day for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

The ENLIVEN study met its primary endpoint of overall response rate. In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

About TGCT (PVNS/GCT-TS)

Tenosynovial giant cell tumor (TGCT), also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.[1], [2], [3]

While the exact incidence of TGCT is not known, it is estimated that the incidence of TGCT is 11 to 50 cases per million person-years, based on studies from three countries.[4],[5],[6] TGCT is subcategorized into two types: localized, which is more common and accounts for 90 percent of cases, and diffuse, which accounts for 10 percent of cases.5,6 Primary treatment of TGCT includes surgery to remove the tumor. However, in patients with a recurrent, difficult to treat, or diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove or might not be amenable to improvement with surgery. Additional surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments, and reduced quality of life and amputation may be considered.[7],[8],[9]

Recurrence rates for localized TGCT are estimated to be up to 15 percent following complete resection.2,[10],[11],[12] Diffuse TGCT recurrence rates are estimated to be about 20 percent to 50 percent following complete resection.3,10,[13] TGCT affects all age groups; the diffuse type on average occurs most often in people below the age of 40 and the localized type typically occurs in people between 30 and 50 years old.1,4,5,6

About Pexidartinib

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib has been granted Priority Review for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery, Breakthrough Therapy designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity, and Orphan Drug designation for the treatment of PVNS/GCT-TS by the U.S. Food and Drug Administration (FDA). Pexidartinib also has received Orphan Drug designation from the European Commission for the treatment of TGCT.

On January 31, 2019, the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) recognized "Progress in Treating Rare Cancers" as the "Advance of the Year," and selected pexidartinib as one of five significant advancements in rare disease treatment, calling it the first promising investigational therapy for TGCT.

Pexidartinib is an investigational compound that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: [fam-] trastuzumab deruxtecan, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD acute myeloid leukemia (AML); and pexidartinib, an oral CSF1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

On April 3, 2019 Aileron Therapeutics (NASDAQ: ALRN), the clinical-stage leader in the field of stabilized cell-permeating peptides to treat cancer and other diseases, reported the closing of its previously announced private placement of Aileron common stock and warrants, resulting in gross proceeds of $26 million, before deducting placement agent fees and offering expenses, and excluding the exercise of any warrants (Press release, Aileron Therapeutics, APR 3, 2019, View Source [SID1234535002]).

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The private placement was led by Satter Medical Technology Partners, L.P. Additional participants included Jennison Associates (on behalf of certain clients) and an undisclosed institutional investor, in addition to other new and existing investors.

In connection with this financing, Aileron also announced that Dr. Nolan Sigal, a Partner at Satter, has joined Aileron’s Board of Directors.

Dr. Sigal has served as a partner at Satter Management, a private investment firm, since January 2018. From March 2008 to December 2017, Dr. Sigal was the president and chief executive officer of Tunitas Therapeutics, Inc., a private biopharmaceutical company. Prior to 2008, Dr. Sigal held various leadership positions with several public and private pharmaceutical and biotechnology companies, including Merck & Company, Trellis, Cytokinetics, and Pharmacopeia. Dr. Sigal received an A.B. from Princeton University and an M.D. and Ph.D. from the University of Pennsylvania School of Medicine.

"I believe that the application of Aileron’s proprietary peptide drug, ALRN-6924, in the indications of MDM2-amplified tumors (with Pfizer’s Ibrance) and myelopreservation represent compelling opportunities. As a member of the Board of Directors, I look forward to helping the Company as it seeks to create value for its shareholders through the advancement of these programs," stated Nolan Sigal, M.D., Ph.D.

"We expect that the proceeds from this closing will enable Aileron to achieve key clinical data readouts" said Dr. Manuel Aivado, M.D, Ph.D., CEO & President of Aileron. "We expect the addition of Dr. Sigal to our Board of Directors to play an important role in our success. His extensive research experience as an executive in the biotech industry makes him a welcome addition to the Aileron team."

In the private placement the Company sold 11,838,582 units, consisting of 11,838,582 shares of common stock and associated warrants to purchase 11,838,582 shares of common stock, for a combined price of $2.01 per unit. In addition, the Company also sold 1,096,741 units, consisting of pre-funded warrants to purchase 1,096,741 shares of common stock and associated warrants to purchase 1,096,741 shares of common stock, for a combined price of $2.01 per unit.

William Blair & Company, L.L.C. acted as sole placement agent in connection with the financing.

Aileron expects to use the net proceeds from the financing to fund the further advancement of its ALRN-6924 clinical trials and research programs, including its ongoing clinical trial collaboration with Pfizer testing ALRN-6924 in combination with palbociclib in MDM2-amplified cancers and its planned Phase 1b/2 clinical trial to evaluate ALRN-6924 as a myelopreservative agent to protect against chemotherapy-induced toxicity. This use of proceeds reflects Aileron’s decision to cease enrollment and clinical development in AML/MDS in light of the Company’s resources and its re-assessment of the commercial opportunities in AML/MDS considering the rapidly evolving competitive landscape in this field.

The securities sold in the private placement have not been registered under the Securities Act of 1933, as amended (the "Securities Act"), or applicable state securities laws, and accordingly may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act and such applicable state securities laws. Aileron has agreed to file a registration statement with the Securities and Exchange Commission registering the resale of the shares of common stock issued in the private placement and the shares of common stock issuable upon the exercise of the warrants issued in the private placement.

This release does not constitute an offer to sell or the solicitation of an offer to buy the securities, nor shall there be any sale of the securities in any state in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state. Any offering of the securities under the resale registration statement will only be by means of a prospectus.

On April 3, 2019 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that data from pre-clinical studies supporting the potential of BP1003, a novel liposome-incorporated STAT3 oligodeoxynucleotide inhibitor, for the treatment of pancreatic cancer, non-small cell lung cancer (NSCLC) and acute myelogenous leukemia (AML) were presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 today in Atlanta, GA (Press release, Bio-Path Holdings, APR 3, 2019, View Source [SID1234535001]).

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The poster, entitled "BP1003, a Novel Liposome-Incorporated STAT3 Antisense Oligodeoxynucleotide Inhibitor," was presented by Ana Tari Ashizawa, Ph.D., Vice President of Research and Development at Bio-Path.

The poster highlights four antisense oligo sequences directed against STAT3 mRNA identified by Bio-Path and manufactured using DNAbilize antisense RNAi nanoparticle technology. Cell viability tests and Western blots were conducted to determine the inhibitory effects of liposome-incorporated STAT3 antisense oligo on NSCLC and AML cells. An ex vivo live tissue sensitivity assay (LTSA) was performed with a panel of 20 pancreatic ductal adenocarcinoma (PDAC) patient-derived xenografts (PDX) to study the overall activity of BP1003 alone, and in combination with gemcitabine. Using previously defined criteria, tissue slice viability inhibition greater than 30% and with a p<0.05 was considered to be a response. For validation of ex vivo results, PDAC PDX tumor bearing mice were administered BP1003 and gemcitabine twice a week for 28 days. Tumor volumes were monitored for up to 49 days.

The most potent liposome-incorporated STAT3 antisense sequence in decreasing NSCLC cell viability was selected as the drug candidate BP1003. Further validation in AML cells demonstrated that BP1003 inhibited cell viability and STAT3 protein expression. In the ex vivo LTSA assay, BP1003 at a dose of 10 µM significantly inhibited the tissue slice viability in 9 out of 18 PDAC PDXs by more than 30% (p<0.05). The combination of BP1003 and gemcitabine further enhanced ex vivo efficacy of BP1003 in a subset of PDXs. In the in vivo study with PDAC PDX models, a combination of BP1003 and gemcitabine caused tumor regression during the 28-day drug treatment period. This anti-cancer activity was maintained for another 21 days, even when drug treatment had ceased.

Preclinical pancreatic cancer models demonstrated that BP1003 successfully penetrated the stroma into pancreatic tumors. As previously reported, Bio-Path’s lead drug candidate, prexigebersen, has been tested in the above-described ex vivo pancreatic cancer preclinical model, and the results also demonstrated that prexigebersen penetrated the pancreatic tumors. Finally, the results in pancreatic cancer showed that BP1003 inhibited tumor slice viability in 9 of 18 PDAC PDXs.

"We believe these data suggest that between our two drug candidates, BP1003 and prexigebersen, Bio-Path will be able to treat human pancreatic tumors. The Company expects to initiate a Phase I study of prexigebersen for the treatment of solid tumors in 2019, including a cohort of metastatic pancreatic cancer patients. We plan to complete Investigational New Drug (IND) enabling studies in 2019 and to file an IND application for a Phase I study of BP1003 for the treatment of pancreatic cancer in 2020," stated Peter Nielsen, Chief Executive Officer of Bio-Path.

"We developed BP1003, a novel liposome-incorporated STAT3 antisense oligodeoxynucleotide, as a specific inhibitor of STAT3 as it is thought to be one of the most important genes involved with a variety of cancers. STAT3 is considered to be an undruggable target, which has hampered the development of a therapy for it. Inhibition of STAT3 requires a systemic RNAi solution, such as DNAbilize, in order to exert its anti-cancer activity," noted Dr. Tari Ashizawa.

"These data are very encouraging and suggest that our two drug candidates, BP1003 and prexigebersen, are active against pancreatic cancer which is often treatment refractory and lethal. As with prexigebersen, studies to date have shown BP1003 to be generally safe and well-tolerated in preclinical models. We believe there is a great potential for the additional development of BP1003 as a treatment for NSCLC, AML and a variety of metastatic cancers," added Mr. Nielsen.

About Signal Transducer and Activator of Transcription 3 (STAT3)

Signal Transduction and Activator of Transcription-3 (STAT3), though typically inactive in normal cells, is aberrantly active in cancer cells. The abilities of tumor cells to proliferate uncontrollably, resist apoptosis, induce vasculature formation, and invade distant organs are well-recognized hallmarks of cancer. STAT3 is a regulator of the genes involved in these cancer processes. More recently, the capability of tumors to evade immune surveillance and avoid destruction by the immune system has also gained significant acceptance in the cancer research field. STAT3, which is a point of convergence for many oncogenic pathways, has emerged as a critical mediator of tumor immune evasion at multiple levels.

Activation of STAT3 has been found in many types of cancers, including NSCLC, AML, and PDAC. Activation of STAT3 correlates with poor clinical outcome, high grade disease and metastasis, and has been linked with resistance to chemotherapy, including gemcitabine, considered a standard-of-care agent for advanced PDAC. Therefore, inhibition of STAT3 in combination with chemotherapy is expected to produce enhanced clinical benefit.

On April 3, 2019 Sangamo Therapeutics, Inc. (Nasdaq: SGMO) reported that it has commenced an underwritten public offering of shares of its common stock (Press release, Sangamo Therapeutics, APR 3, 2019, View Source [SID1234534996]). All of the shares are being offered by Sangamo. In addition, Sangamo expects to grant the underwriters of the offering a 30-day option to purchase additional shares of its common stock at the public offering price, less the underwriting discounts and commissions. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering will be completed, or as to the actual size or terms of the offering.

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Sangamo anticipates using the net proceeds from the offering for working capital and other general corporate purposes, including support for its own and its partnered gene therapy, genome editing, cell therapy and gene regulation product candidates and research programs, its manufacturing facilities and other business development activities.

Cowen and Company, LLC, Wells Fargo Securities, LLC and Barclays Capital Inc. are acting as joint book-running managers for the offering.

A registration statement relating to the shares was previously filed with and became effective by rule of the Securities and Exchange Commission. The offering is being made solely by means of a prospectus. A preliminary prospectus supplement and accompanying prospectus relating to the offering will be filed with the Securities and Exchange Commission and will be available on the Securities and Exchange Commission’s website located at View Source A copy of the preliminary prospectus supplement and accompanying prospectus relating to the offering, when available, may be obtained from Cowen and Company, LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at (631) 274-2806; or from Wells Fargo Securities, LLC, Attention: Equity Syndicate Department, 375 Park Avenue, New York, New York 10152, or by telephone at (800) 326-5897 or email to [email protected]; or from Barclays Capital Inc., c/o Broadridge Financial Solutions, Attn: Prospectus Department, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at (888) 603-5847, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On April 3, 2019 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with unmet needs in hematology and oncology, reported preclinical data for its novel oral Cdc7 inhibitor, SRA141, in a late-breaking poster being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia (Press release, Sierra Oncology, APR 3, 2019, View Source [SID1234534995]).

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"Prior studies demonstrated that SRA141 potently and selectively inhibits Cdc7, resulting in robust anti-tumor efficacy in colorectal xenograft models, however, the compound’s exact mechanism of action has not been characterized previously. Our findings reveal a potentially novel mechanism of cytotoxicity for Cdc7 inhibitors that is distinct from other agents, and thus SRA141 may herald a new class of cancer therapeutic agents with a differentiated anti-tumor profile," said Dr. Eric J. Brown, Associate Professor of Cancer Biology at the Perelman School of Medicine of the University of Pennsylvania, and member of Sierra’s DNA damage response (DDR) Advisory Committee.

"SRA141 does not induce G1 cell cycle arrest or replication stress, thereby distinguishing it from other agents such as palbociclib or SRA737. Rather, SRA141 alters DNA replication dynamics and delays cell cycle progression, ultimately resulting in caspase-dependent cell death associated with mitotic accumulation. Promisingly, we believe we have shown for the first time that this mechanism appears to synergize with anti-apoptotic drugs, such as venetoclax, and dysregulators of mitosis, such as barasertib. This differentiated mechanism of action supports a potentially unique spectrum of clinical opportunities for SRA141 as both monotherapy and in combination with pro-apoptotic and mitotic disrupting agents," said Dr. Christian Hassig, Chief Scientific Officer, Sierra Oncology.

SRA141 AACR (Free AACR Whitepaper) Late-Breaking Poster:
Date/Time: Wednesday, April 3rd from 8:00 am to 12:00 pm ET
Session: Late-Breaking Research: Molecular and Cellular Biology / Genetics 2
Title: CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics.
Authors: Veena Jagannathan, Snezana Milutinovic, Ryan J. Hansen, Bryan Strouse, Christian Hassig and Eric J. Brown.
Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 41, Poster #5

The poster will be made available on the company’s website at www.sierraoncology.com.

About SRA141 targeting Cdc7
SRA141 is a novel, potent, orally bioavailable selective inhibitor of Cell division cycle 7 (Cdc7) kinase. Owing to its important role in DNA replication, and its overexpression in various neoplasms, Cdc7 is an attractive therapeutic target with emerging clinical validation in oncology.

Cdc7, together with its partner proteins Dbf4 or Drf1, is responsible for activating DNA replication origin firing during S-phase through phosphorylation and activation of the MCM2-7 helicase. Cdc7 also has functions within the DNA Damage Response (DDR) and mitosis. Over-expression of Cdc7 and its partner proteins is correlated with unfavorable clinical outcomes and poor survival in a broad range of solid tumors and hematological malignancies.

SRA141 has been shown to cause cancer cell death in a p53-independent manner and to induce tumor regression or stasis in a variety of in vivo cancer models, including complete and partial regressions in animal models of colorectal cancer.

An Investigational New Drug Application (IND) filing has been accepted by the U.S. Food and Drug Administration (FDA) for SRA141, and Sierra Oncology has prepared for a potential Phase 1/2 trial of the drug candidate in patients with advanced colorectal cancer. Sierra Oncology is currently evaluating the optimal timing to commence this trial within the context of its recently expanded portfolio.

Sierra Oncology retains the global commercialization rights to SRA141